Current observations support the existence of at least two distinct pathways for control of cGMP in kidney: one dependent upon the presence of extracellular Ca2 ion, Na ion and O2 availability and one relatively unaffected by these factors. Initial observations indicate that the extracellular cations Ca 2 ion and Na ion may serve as key signals for modulation of cellular cGMP in kidney through actions dependent on the presence of O2. It is possible that cellular cGMP in turn influences the transport of Ca2 ion and Na ion in kidney. Current data also support the existence of important regional differences in the properties and regulation of the guanylate cyclase -cGMP systems in kidney. In cortex, guanylate cyclase is found predominantly in the soluble form, whereas in inner medulla the enzyme is largely in the particulate form. In inner medulla alterations in osm lality have marked effects on basal and hormone responsive cGMP. The objectives of the present study are: a) to define the properties and regulation of guanylate cyclase from different regions of the kidney; b) to examine the factors including extracellular cations, osmolality and O2 regulating the activity of renal guanylate cyclase and cGMP systems; c) to study the relationship between Ca2 ion and O2 dependence in expression of the actions of agonists of cGMP in kidney. The role of Ca2 ion and O2 dependent prostaglandin synthesis are being explored; d) to examine the possible biologic role of cGMP in control of Ca2 ion-dependent gluconeogenesis, and Ca2 ion homeostasis in renal tubules; e) to study cGMP interactions with cAMP and Ca2 ion. The proposed investigation should further understanding of the regulation of cGMP metabolism in renal tissues and its biol gic actions. It should also provide further insight into control of cGMP and cAMP metabolism in inner medulla under the unique conditions (low O2 tension, high osmolality) which pertain in this tissue in vivo.